4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidinyl-acetyl)piperazine

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidinyl-acetyl)piperazine
• 英文别名: 4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidine-acetyl)piperazine；1-[4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)piperazin-1-yl]-2-piperidin-4-ylethanone
• 化学式: C₂₄H₂₉ClN₄OS
• 分子量: 457.039
• InChiKey: URIAEERZIAFNMX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  73.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidinyl-acetyl)piperazine 、 三甲基硅基异氰酸酯 在 碳酸氢钠 、 水 、 二氯甲烷 、 Brine 、 Sodium sulfate-III 、 crude residue 、 methanol-dichloromethane 、 Dichloromethane methanol ammonium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 90.0h， 以the pure product was obtained (295 mg, 66%)的产率得到4-[2-[4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-1-piperidinecarboxamide
  参考文献：
  名称：

  Tricyclic compounds having activity as RAS-FPT inhibitors

  摘要：

  公式I的化合物：##STR1## 其中：X.sup.1是氢，卤素，CF.sub.3，硝基，NH.sub.2或低烷基；每个X.sup.2独立地选自由氢，卤素，低烷氧基和低烷基组成的群；n为1或2；Y选自S（O）.sub.p，O和NR.sup.5组成的群，其中p为0，1或2，R.sup.5为氢，烷基，芳基，环烷基，低烷氧羰基，氨基羰基或酰基；R.sup.1和R.sup.2，可以相同也可以不同，选自氢和低烷基组，或者当Y为NR.sup.5时，它们可以结合成一个氧原子；A…为C=，CH-或N-；R为--CZ--Y.sup.1--Y.sup.2--R.sup.3，其中：Z为O，=CH-CN或=N-CN；Y.sup.1和Y.sup.2中的一个是键，--CO--，O，S或--NR.sup.4--，另一个为（CH.sub.2）.sub.m，其中m为0或1到4的整数，R.sup.4为H或烷基，但当Z为O且m为0时，Y.sup.1或Y.sup.2选自--CO--，O，S或--NR.sup.4；R.sup.3为芳基，杂芳基或杂环烷基，但当Z为=N-CN时，R.sup.3也可以是低烷基；它们的药学上可接受的酸盐具有Ras-FPT抑制剂的活性。它们可以用于制备药物组合物，用于抑制细胞的异常生长和抑制增殖性疾病。还披露了它们的制备过程和有用的中间体。

  公开号：

  US06130229A1
• 作为产物：
  描述：

  8-Chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-one 在 sodium tetrahydroborate 、 氯化亚砜 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 31.67h， 生成 4-(8-Chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-1-(4-piperidinyl-acetyl)piperazine
  参考文献：
  名称：

  Inhibitors of farnesyl protein transferase. synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system

  摘要：

  Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00439-9

文献信息

• TRICYCLIC COMPOUNDS HAVING ACTIVITY AS Ras-FPT INHIBITORS
  申请人：SCHERING CORPORATION

  公开号：EP1021448B1

  公开（公告）日：2003-05-02
• US6130229A
  申请人：——

  公开号：US6130229A

  公开（公告）日：2000-10-10
• [EN] TRICYCLIC COMPOUNDS HAVING ACTIVITY AS Ras-FPT INHIBITORS<br/>[FR] COMPOSES TRICYCLIQUES PRESENTANT UNE ACTIVITE D'INHIBITEURS DE LA Ras-FPT
  申请人：SCHERING CORPORATION

  公开号：WO1998015556A1

  公开（公告）日：1998-04-16

  (EN) Compounds of formula (I), wherein: X1 is hydrogen, halogen, CF3, nitro, NH2 or lower alkyl; each X2 is independently selected from the group consisting of hydrogen, halogen, lower alkoxy and lower alkyl; n is 1 or 2; Y is selected from the group consisting of S(O)p, O, and NR5, wherein p is 0, 1 or 2, and R5 is hydrogen, alkyl, aryl, cycloalkyl, loweralkoxycarbonyl, aminocarbonyl or acyl; R1 and R2, which may be the same or different, are selected from the group consisting of hydrogen and lower alkyl groups, or taken together can form an oxygen atom when Y is NR5; A..... is C=, CH- or N-; R is -CZ-Y1-Y2-R3, wherein: Z is O, =CH-CN, or =N-CN; one of Y1 and Y2 is a bond, -CO-, O, S, or -NR4-, and the other is (CH2)m, where m is 0 or an integer of 1 to 4, and R4 is H or alkyl, with the previso that when Z is O and m is 0 then Y1 or Y2 is selected form -CO-, O, S, or -NR4; R3 is aryl, heteroaryl or heterocycloalkyl, with proviso that R3 can also be lower alkyl when Z is =N-CN; and their pharmaceutically acceptable acid additions salts; have activity as Ras-FPT inhibitors. They can be used, e.g., in pharmaceutical compositions, for inhibiting the abnormal growth of cells and for inhibiting proliferative diseases. Processes for their preparation, and useful intermediates, are also disclosed.(FR) L'invention porte sur des composés de formule (I) dans laquelle: X1 est H, halogène, CF3, nitro, NH2, ou alkyle inférieur; chacun des X2 est choisi indépendamment parmi H, alkoxy inférieur, ou alkyle inférieur; n est 1 ou 2; Y est choisi parmi S(O)p, O et NR5, p étant 0, 1 ou 2, et R5 étant H, alkyle, aryle, cycloalkyle, alkoxy inférieur carbonyle, aminocarbonyle ou acyle; R1 et R2 qui peuvent être identiques ou différents sont choisis parmi des groupes H ou alkyle inférieur, ou peuvent former ensemble un atome d'oxygène lorsque Y est NR5; A..... est C=, CH- ou N-; R est -CZ-Y1-Y2-R3, où Z est O, =CH-CN, ou =N-CN; l'un des Y1 et Y2 est une liaison, -CO-, O, S, ou -NR4-, et l'autre est (CH2)m, m étant = ou un entier de 1 à 4, et R4 étant H ou alkyle sous réserve que si Z est O, et m est 0, Y1 et Y2 soient choisis parmi -CO-, O, S, ou -NR4; R3 est aryle, hétéroaryle ou hétérocycloalkyle, sous réserve que R3 puisse également être alkyle inférieur lorsque Z est =N-CN. L'invention porte également sur leurs sels acidifiants pharmacocompatibles qui peuvent être utilisés par exemple dans des préparations pharmaceutiques pour inhiber la croissance cellulaire anormale et les maladies proliférantes; elle porte en outre sur leur préparation et sur des intermédiaires utiles.
• Inhibitors of farnesyl protein transferase. synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system
  作者：Ronald Wolin、Michael Connolly、Joseph Kelly、Jay Weinstein、Stuart Rosenblum、Adriano Afonso、Linda James、Paul Kirschmeier、W. Robert Bishop

  DOI：10.1016/s0960-894x(98)00439-9

  日期：1998.9

  Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol. (C) 1998 Elsevier Science Ltd. All rights reserved.
• Tricyclic compounds having activity as RAS-FPT inhibitors
  申请人：Schering Corporation

  公开号：US06130229A1

  公开（公告）日：2000-10-10

  Compounds of Formula I: ##STR1## wherein: X.sup.1 is hydrogen, halogen, CF.sub.3, nitro, NH.sub.2 or lower alkyl; each X.sup.2 is independently selected from the group consisting of hydrogen, halogen, lower alkoxy and lower alkyl; n is 1 or 2; Y is selected from the group consisting of S(O).sub.p, O, and NR.sup.5, wherein p is 0, 1 or 2, and R.sup.5 is hydrogen, alkyl, aryl, cycloalkyl, loweralkoxycarbonyl, aminocarbonyl or acyl; R.sup.1 and R.sup.2, which may be the same or different, are selected from the group consisting of hydrogen and lower alkyl groups, or taken together can form an oxygen atom when Y is NR.sup.5 ; A . . . is C=, CH-- or N--; R is --CZ--Y.sup.1 --Y.sup.2 --R.sup.3, wherein: Z is O, =CH--CN, or =N--CN; one of Y.sup.1 and Y.sup.2 is a bond, --CO--, O, S, or --NR.sup.4 --, and the other is (CH.sub.2).sub.m, where m is 0 or an integer of 1 to 4, and R.sup.4 is H or alkyl, with the proviso that when Z is O and m is 0 then Y.sup.1 or Y.sup.2 is selected from --CO--, O, S, or --NR.sup.4 ; R.sup.3 is aryl, heteroaryl or heterocycloalkyl, with the proviso that R.sup.3 can also be lower alkyl when Z is =N--CN; and their pharmaceutically acceptable acid addition salts; have activity as Ras-FPT inhibitors. They can be used, e.g., in pharmaceutical compositions, for inhibiting the abnormal growth of cells and for inhibiting proliferative diseases. Processes for their preparation, and useful intermediates, are also disclosed.

  公式I的化合物：##STR1## 其中：X.sup.1是氢，卤素，CF.sub.3，硝基，NH.sub.2或低烷基；每个X.sup.2独立地选自由氢，卤素，低烷氧基和低烷基组成的群；n为1或2；Y选自S（O）.sub.p，O和NR.sup.5组成的群，其中p为0，1或2，R.sup.5为氢，烷基，芳基，环烷基，低烷氧羰基，氨基羰基或酰基；R.sup.1和R.sup.2，可以相同也可以不同，选自氢和低烷基组，或者当Y为NR.sup.5时，它们可以结合成一个氧原子；A…为C=，CH-或N-；R为--CZ--Y.sup.1--Y.sup.2--R.sup.3，其中：Z为O，=CH-CN或=N-CN；Y.sup.1和Y.sup.2中的一个是键，--CO--，O，S或--NR.sup.4--，另一个为（CH.sub.2）.sub.m，其中m为0或1到4的整数，R.sup.4为H或烷基，但当Z为O且m为0时，Y.sup.1或Y.sup.2选自--CO--，O，S或--NR.sup.4；R.sup.3为芳基，杂芳基或杂环烷基，但当Z为=N-CN时，R.sup.3也可以是低烷基；它们的药学上可接受的酸盐具有Ras-FPT抑制剂的活性。它们可以用于制备药物组合物，用于抑制细胞的异常生长和抑制增殖性疾病。还披露了它们的制备过程和有用的中间体。